Methylmalonic Acidemia

Moderna share price took a blow as CEO Stéphane Bancel outlined a diminished guidance for 2025. Credit: Boston Globe/ Getty Images Moderna lost more than 20% of its value on the stock market as the company delivered slashed revenue guidance for 2025, stressing savings as key to its goal of balancing cash flow by 2028. Ahead of CEO Stéphane Bancel’s address at the JP Morgan Healthcare Conference 2025, being held in San Francisco, the company announced business and pipeline updates that emphasised the company’s conservative tack, with cash cost estimations projected to drop by around $1bn from 2024. The company’s stock was down 21% when the market opened that day [13 January] and remains in the same range a day later. Moderna, which took centre stage during the pandemic, has not had a share price this low since April 2020. The company’s strategy moving forward will centre on driving sales from its currently marketed products; its Covid-19 vaccine Spikevax, approved by the US Food and Drug Administration (FDA) in January 2022, and its RSV vaccine mRESVIA , which received FDA approval in May 2024. Moderna generated $3bn–$3.1bn in total product sales in 2024, below its $3.5bn target. Bancel said these revenues are expected to further drop to $1.5bn–$2.5bn in 2025. In an effort to maintain the longevity of profits gained during the Covid-19 pandemic, the company has enacted a sweeping program of cost savings, including cutting several clinical programmes . Reduced investment in R&D will continue into 2025, according to Bancel, who stated Moderna will seek to reduce net cash use from around $4bn in 2024 to approximately $3.5bn during 2025, with the goal of attaining a net even cash flow by 2028. However, the company expects up to three new approvals in the next year for its Covid-19 vaccine mRNA-1283, and the combined flu-Covid-19 vaccine mRNA-1083, as well as its RSV vaccine mRNA-1345, all of which saw positive Phase III data readouts in 2024. Moderna also saw positive Phase I/II data with other infectious disease vaccines, namely the mRNA-1189 for Epstein-Barr virus (EBV), mRNA-1468 for varicella-zoster virus (VZV) to prevent shingles, and mRNA-1403 for norovirus. A Phase III trial (NCT06592794), is now underway in the US for mRNA-1403 for which Bancel stated a data readout is expected in 2025 or 2026. Alongside infectious disease vaccines, candidates in development for cancers and metabolic diseases are positioned to be part of Moderna’s future marketed drugs portfolio. These include mRNA-4157, an individualised neoantigen therapy in a Phase II trial with Merck & Co’s Keytruda (pembrolizumab) against metastatic melanoma (NCT03897881) and mRNA-4359, an immune checkpoint modulator targeting PDL-1 and IDO1 for which positive Phase I/II (NCT05533697) data was presented at ESMO 2024 . Like other pharma companies, Moderna is also attempting to break into the metabolic disease space to find new revenues. mRNA-3927 and mRNA-3705 are in Phase II trials for propionic acidemia (NCT05130437) and methylmalonic acidemia (NCT05295433), and along with several other vaccines in melanoma, norovirus, CMV, and Covid-19 are expected to see FDA approval by 2027.

Data demonstrate engineered tRNA from company’s first development candidate restores protein production to clinically meaningful levels in two disease models driven by the same premature termination codon CAMBRIDGE, MA, USA I December 9, 2024 I Alltrna , a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announced the presentation of new preclinical data, including of the company’s first tRNA development candidate, AP003. AP003 is a chemically modified, engineered tRNA oligonucleotide in a clinically validated, liver-directed lipid nanoparticle (LNP) that can readthrough the arginine to TGA (Arg-TGA) premature termination codon (PTC). A single dose of AP003 tRNA showed robust in vivo restoration of protein production to clinically meaningful levels in two transgenic Stop Codon Disease mouse models, methylmalonic acidemia (MMA) and phenylketonuria (PKU). The data were presented at the Nature Conference: RNA at the Bench and Bedside IV, taking place December 9-11 at The Salk Institute in La Jolla, California. “These data represent an important milestone for Alltrna, demonstrating robust in vivo activity and clinically relevant protein restoration across two disease models representing two different inborn errors of metabolism driven by the same premature termination codon,” said Michelle C. Werner, CEO of Alltrna and CEO-Partner at Flagship Pioneering. “We believe these data support the potential for a basket approach to developing AP003 for the treatment of many rare genetic liver diseases caused by an Arg-TGA PTC, including the organic acidemias and aminoacidopathies represented by our MMA and PKU Stop Codon Disease mouse models. We look forward to advancing our IND-enabling studies for AP003.” In an MMA Stop Codon Disease mouse model, developed by Alltrna and collaborators, a single dose of the tRNA component of AP003 (tRNA-3) in a LNP delivery system restored in vivo protein levels of methylmalonyl-CoA mutase (MMUT) to approximately 25% of wildtype levels at Day 4, well above the 1-2% protein rescue considered to be clinically meaningful in MMA by key opinion leaders. Protein levels remained above 1-2% of wildtype 14 days after dosing, which was the longest time point tested. In a new Stop Codon Disease mouse model of PKU, developed by Alltrna, a single dose of AP003 demonstrated phenylalanine hydroxylase (PAH) restoration to 7% of wildtype levels within 72 hours, exceeding the clinically relevant 3% protein rescue target defined by key opinion leaders. Further, this PAH protein restoration resulted in a meaningful 76% reduction of phenylalanine (Phe) levels from baseline, as PAH is the enzyme responsible for breaking down Phe. When PAH is mutated or deficient, Phe accumulates to toxic levels, causing the hallmark elevated Phe levels observed in PKU. “Based on tRNA’s critical role in protein translation, a single tRNA medicine is uniquely positioned to address multiple diseases that have a shared mutation. We are excited to see that our engineered tRNA can in fact achieve significant restoration of protein production above clinically relevant target levels in both MMA and PKU, where a premature termination codon would otherwise create a truncated or missing protein,” said Chris Henderson, Ph.D., Chief Scientific Officer of Alltrna. “In addition, to our knowledge, these are the first preclinical data with a tRNA candidate demonstrating that protein restoration leads to meaningful changes in levels of a clinical biomarker (Phe) that is recognized as a registrational endpoint in humans.” Dr. Henderson continued, “We are delighted to have generated such promising in vivo data in two models of Stop Codon Disease. The fact that a single engineered tRNA acting on the same premature termination codon can show readthrough and protein restoration in two distinct genetic contexts provides support for Alltrna’s vision of treating patients carrying the same PTC across different diseases in a given tissue. As a first example, we look forward to developing AP003 through a basket approach as a novel treatment for inborn errors of metabolism affecting the liver.” About AP003 AP003 is a chemically modified, engineered tRNA oligonucleotide encapsulated in a clinically validated, liver-directed lipid nanoparticle that is in development for the treatment of patients with liver Stop Codon Disease that carry an arginine to TGA (Arg-TGA) nonsense mutation in the affected gene. The Arg-TGA mutation occurs when a single base of the arginine-encoding codons, CGA and AGA, mutates to UGA (TGA in DNA), a termination codon for which there is no corresponding amino acid. AP003 is designed to readthrough the premature termination codon to reintroduce arginine into the growing polypeptide chain at the time of RNA-to-protein translation and restore protein production. Arg-TGA is the most frequent nonsense mutation (21-22%) occurring in human genetic diseases. About Stop Codon Disease Stop Codon Disease encompasses thousands of rare and common diseases that stem from premature termination codons (PTC) also called nonsense mutations, where the code for an amino acid has been mutated into a premature “stop” codon. This results in a truncated or shortened protein product with no or altered biological activity that causes disease. Approximately 10% of all people with a genetic disease have Stop Codon Disease, representing approximately 30 million people worldwide. Alltrna is engineering tRNA medicines that can read these PTC mutations and deliver the desired amino acid, thereby restoring the production of the full-length protein. About Alltrna Alltrna unlocks tRNA biology to treat disease. The company’s platform incorporates AI/ML tools to develop and deliver diverse programmable molecules with broad therapeutic potential. Alltrna has an unprecedented opportunity to advance a single tRNA medicine to readthrough premature stop codons and unify treatment across a wide range of diseases with the same underlying genetic mutations. Alltrna was founded in 2018 by Flagship Pioneering. For more info, visit www.alltrna.com . SOURCE: Alltrna

Data demonstrate engineered tRNA from company's first development candidate restores protein production to clinically meaningful levels in two disease models driven by the same premature termination codon CAMBRIDGE, Mass., Dec. 9, 2024 /PRNewswire/ -- Alltrna, a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announced the presentation of new preclinical data, including of the company's first tRNA development candidate, AP003. AP003 is a chemically modified, engineered tRNA oligonucleotide in a clinically validated, liver-directed lipid nanoparticle (LNP) that can readthrough the arginine to TGA (Arg-TGA) premature termination codon (PTC). A single dose of AP003 tRNA showed robust in vivo restoration of protein production to clinically meaningful levels in two transgenic Stop Codon Disease mouse models, methylmalonic acidemia (MMA) and phenylketonuria (PKU). The data were presented at the Nature Conference: RNA at the Bench and Bedside IV, taking place December 9-11 at The Salk Institute in La Jolla, California. "These data represent an important milestone for Alltrna, demonstrating robust in vivo activity and clinically relevant protein restoration across two disease models representing two different inborn errors of metabolism driven by the same premature termination codon," said Michelle C. Werner, CEO of Alltrna and CEO-Partner at Flagship Pioneering. "We believe these data support the potential for a basket approach to developing AP003 for the treatment of many rare genetic liver diseases caused by an Arg-TGA PTC, including the organic acidemias and aminoacidopathies represented by our MMA and PKU Stop Codon Disease mouse models. We look forward to advancing our IND-enabling studies for AP003." In an MMA Stop Codon Disease mouse model, developed by Alltrna and collaborators, a single dose of the tRNA component of AP003 (tRNA-3) in a LNP delivery system restored in vivo protein levels of methylmalonyl-CoA mutase (MMUT) to approximately 25% of wildtype levels at Day 4, well above the 1-2% protein rescue considered to be clinically meaningful in MMA by key opinion leaders. Protein levels remained above 1-2% of wildtype 14 days after dosing, which was the longest time point tested. In a new Stop Codon Disease mouse model of PKU, developed by Alltrna, a single dose of AP003 demonstrated phenylalanine hydroxylase (PAH) restoration to 7% of wildtype levels within 72 hours, exceeding the clinically relevant 3% protein rescue target defined by key opinion leaders. Further, this PAH protein restoration resulted in a meaningful 76% reduction of phenylalanine (Phe) levels from baseline, as PAH is the enzyme responsible for breaking down Phe. When PAH is mutated or deficient, Phe accumulates to toxic levels, causing the hallmark elevated Phe levels observed in PKU. "Based on tRNA's critical role in protein translation, a single tRNA medicine is uniquely positioned to address multiple diseases that have a shared mutation. We are excited to see that our engineered tRNA can in fact achieve significant restoration of protein production above clinically relevant target levels in both MMA and PKU, where a premature termination codon would otherwise create a truncated or missing protein," said Chris Henderson, Ph.D., Chief Scientific Officer of Alltrna. "In addition, to our knowledge, these are the first preclinical data with a tRNA candidate demonstrating that protein restoration leads to meaningful changes in levels of a clinical biomarker (Phe) that is recognized as a registrational endpoint in humans." Dr. Henderson continued, "We are delighted to have generated such promising in vivo data in two models of Stop Codon Disease. The fact that a single engineered tRNA acting on the same premature termination codon can show readthrough and protein restoration in two distinct genetic contexts provides support for Alltrna's vision of treating patients carrying the same PTC across different diseases in a given tissue. As a first example, we look forward to developing AP003 through a basket approach as a novel treatment for inborn errors of metabolism affecting the liver." About AP003 AP003 is a chemically modified, engineered tRNA oligonucleotide encapsulated in a clinically validated, liver-directed lipid nanoparticle that is in development for the treatment of patients with liver Stop Codon Disease that carry an arginine to TGA (Arg-TGA) nonsense mutation in the affected gene. The Arg-TGA mutation occurs when a single base of the arginine-encoding codons, CGA and AGA, mutates to UGA (TGA in DNA), a termination codon for which there is no corresponding amino acid. AP003 is designed to readthrough the premature termination codon to reintroduce arginine into the growing polypeptide chain at the time of RNA-to-protein translation and restore protein production. Arg-TGA is the most frequent nonsense mutation (21-22%) occurring in human genetic diseases. About Stop Codon Disease Stop Codon Disease encompasses thousands of rare and common diseases that stem from premature termination codons (PTC) also called nonsense mutations, where the code for an amino acid has been mutated into a premature "stop" codon. This results in a truncated or shortened protein product with no or altered biological activity that causes disease. Approximately 10% of all people with a genetic disease have Stop Codon Disease, representing approximately 30 million people worldwide. Alltrna is engineering tRNA medicines that can read these PTC mutations and deliver the desired amino acid, thereby restoring the production of the full-length protein. About Alltrna Alltrna unlocks tRNA biology to treat disease. The company's platform incorporates AI/ML tools to develop and deliver diverse programmable molecules with broad therapeutic potential. Alltrna has an unprecedented opportunity to advance a single tRNA medicine to readthrough premature stop codons and unify treatment across a wide range of diseases with the same underlying genetic mutations. Alltrna was founded in 2018 by Flagship Pioneering. For more info, visit . Media Contacts Jessica Yingling, Ph.D., Little Dog Communications Inc., [email protected], +1.858.344.8091 Josephine Zorbo, Ph.D., Flagship Pioneering, [email protected] SOURCE Alltrna WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED